The "dopamine hypothesis" of schizophrenia predicts an increased activity of dopamine neurotransmission in the disease. The hypothesis is supported by early observations that drugs, such as amphetamine, with dopamine agonist or dopamine-releasing properties are capable of eliciting a psychosis indistinguishable from acute paranoid schizophrenia.
Schizophrenia is a disorder that is conventionally treated with drugs known as neuroleptics. In the majority of cases, the symptoms of schizophrenia can be treated successfully with so-called "classical" neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D.sub.2 receptors. The fact that classical neuroleptic drugs have an action on dopamine receptors in the brain thus lends credence to the "dopamine hypothesis" of schizophrenia.
Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D.sub.1 receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D.sub.2 receptor subtype, and at least one form of the D.sub.3 receptor subtype, have also been discovered. More recently, the D.sub.4 (Van Tol et al., Nature (London) 350:610 (1991)) and D.sub.5 (Sunahara et al., Nature (London) 350:614 (1991)) receptor subtypes have been described.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms (e.g., Parkinsonian-like symptoms, tardive dyskensia, dystonia) and neuroendocrine (hormonal) disturbances. These side-effects detract from the clinical desirability of classical neuroleptics, and they are believed to be attributable to D.sub.2 receptor blockade in the striatal region of the brain.
It is considered (Van Tol et al., supra; and WO-A-92/10571) that compounds which can interact selectively with the dopamine D.sub.4 receptor subtype, whilst having a less-pronounced action at the D.sub.2 subtype, might be free from, or at any rate less prone to, the side-effects associated with classical neuroleptics, whilst at the same time maintaining a beneficial level of antipsychotic activity. The development of dopamine D4 antagonists has been reviewed recently by Kulagowski and Patel, Curr. Pharm. Design 3, 355-366 (1997).
EPA-0285032 discloses a class of phenylpiperidine compounds which are therapeutically active. These compounds are useful in treating pain conditions and they also have neuroleptic properties. Each of the disclosed compounds contains a phenylpiperidine substructure.
EPA-0259621 describes a genus of therapeutically active piperidine compounds which are useful in treating disease related to decreased cognitive function, such as Alzheimers. The compounds are cholinergic agonists which act on the postsynaptic muscarinic receptors in the forebrain and the hippocampus. This disclosure focuses on the interaction of these compounds with muscarinic receptors, not dopamine receptors.
EPA-0077607 describes a class of piperidine derivatives substituted in the 3-position by a substituted phenyl moiety and on the ring nitrogen atom by inter alia an optionally substituted benzofuryl or benzofuryl-alkyl group. Certain of these compounds are stated to be dopamine agonists, whilst others are alleged to be dopamine antagonists. There is no suggestion that the compounds described therein might be potent antagonists of the human dopamine D.sub.4 receptor subtype. There is also no teaching that they might have a selective affinity for the dopamine D.sub.4 receptor subtype over other dopamine receptor subtypes, and especially the D.sub.2 subtype. A similar class of benzo[b]furan compounds is disclosed in WO 95/29911.
EPA-0239309 discloses oxadiazole compounds with a substituent in one of the ring carbons with a non-aromatic azacylic or azabicyclic ring system and substituted on the other ring carbon with a substitutent of low lipophilicity having a Rekker f value of not greater than 1.5. These compounds are useful as muscarinic receptor antagonists.
WP 97/30994 describes oxa and thia-diazolic muscarinic receptor antagonists wherein a benzyl alcohol and a piperidine are substituted on the diazole ring.
Drugs which selectively target and bind to the recently recognized dopamine D.sub.4 receptor subclass are promising new treatment modalities for psychotic disorders such as schizophrenia. Drugs which exhibit binding affinities for the D.sub.4 receptor subclass which are greater than their binding affinities for the D.sub.2 subclass will prove therapeutically useful and cause fewer side effects. The present invention provides a class of such D.sub.4 selective agents.